tbuckley/cabot-search huggingface dataset:
OTHR-35. Health-Related Quality of Life and Social Determinants of Health within Children with Brain and Spinal Cord Tumors
Authors: Kelsey Knight, Karl Balsara, Scott Coven
Journal: Neuro-Oncology (2022)

Abstract Social determinants of health (SDOH) have a significant impact on health, well-being, and quality of life (QOL). Validated tools to assess these disparities have been developed but not utilized prospectively in children with central nervous system tumors (CNS). OBJECTIVE: To establish a baseline assessment of health-related quality of life and associated social determinants of health in children with CNS tumors in Indiana. METHOD: We implemented the Pediatric Quality of Life Inventory™ (PedsQL™) for patients (ages 0-21 years) diagnosed with a CNS tumor evaluated in the neuro-oncology clinic from July 2019-January 2022. A higher score is associated with better quality of life. Patient's address was utilized to obtain Area Deprivation Index (ADI) and Child Opportunity Index (COI). ADI allows for rankings of neighborhoods by socioeconomic disadvantage at state or national level (1-10: 1 is least disadvantaged). COI measures the quality of resources in a patients’ community, with five categories ranging from very low- to very high-opportunity. RESULTS: We assessed 107 patients and their parents. The ADI decile within Indiana ranged 1 to 10 (median 5, mean 5.3); national percentile ranged 7 to 100 (median 71, mean 67.3). Overall COI mean was 3, with sub-scores for education - 2.9, health/environment - 2.6, and social/economic - 3.1. The PedsQL™ was completed by 96 parents and 91 patients. Physical mean was 67.4 and 71.2, psychosocial mean 67.8, 68.9, and total mean 67.7, 69.8, respectively. Simple linear regressions demonstrated a correlation between increasing disparity and decreasing quality of life across all dimensions. CONCLUSION: This is one of the first studies to associate a decrease in pediatric quality of life with disparities of social determinants of health. These data demonstrate the need for expanded prospective evaluation to track social determinants of health that may impact on the quality of life in children diagnosed with CNS tumors.
HGG-59. Pediatric high-grade gliomas and the WHO classification on CNS Tumors - Different perspectives of pediatric neuro-oncologists and neuropathologists in the light of recent updates
Authors: Gerrit Gielen, Joshua Baugh, Dannis van Vuurden, Sophie Veldhuijzen van Zanten, Darren Hargrave, Maura Massimino, Veronica Biassoni, Andres Morales la Madrid, Michael Karremann, Maria Wiese, Ulrich Thomale, Geert Janssens, André von Bueren, Pitt Niehusmann, Marco Gessi, Robert Kwiecien, Simon Bailey, Torsten Pietsch, Felipe Andreiuolo
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring following rapid advances in brain tumor genomics and epigenomics. The most significant changes resulted from the introduction of molecularly defined diagnostic criteria in 2016 (revised 4th edition). In 2021 (5th edition), further essential molecular criteria were incorporated. In the present study, we sought to investigate potential differences between specialists in perception of these newly defined molecular subtypes of pediatric high-grade gliomas (pedHGG). METHODS: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to capture the spectrum of viewpoints and possible differences among neuro-oncologists and neuropathologists. RESULTS: 465 participants from 53 countries responded, of which 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%) and 118 experts in other related fields (neurosurgeons, radiotherapists, neuroradiologists and others; 26%). Neuro-oncologists reported having issues with the introduction of new molecular entities, such as the abolishment and renaming of established tumor entities. Neuropathologists did not define these problems to the same extent. However, both groups felt that in the 2016 version, less relevant or insufficient diagnostic definitions were available for pedHGG. Within the 2021 WHO classification, a substantial improvement was perceived regarding the definition of pedHGG entities. However, some issues of high clinical relevance, like the definition of clinical phenotypes such as diffuse intrinsic pontine glioma (DIPG) and gliomatosis cerebri, are yet to be addressed. CONCLUSIONS: Within the WHO classification of pediatric brain tumors, such as high-grade gliomas, rapid changes in nomenclature have been introduced because of substantial improvement in molecular characterization. This study highlights that ongoing cross-talk between advancing classification of pedHGG subtypes and its biological relevance and clinical impact is essential.
Low-risk meningioma: Initial outcomes from NRG Oncology/RTOG 0539
Authors: C Leland Rogers, Stephanie L Pugh, Michael A Vogelbaum, Arie Perry, Lynn S Ashby, Jignesh M Modi, Anthony M Alleman, Igor J Barani, Steve Braunstein, Joseph A Bovi, John F de Groot, Anthony C Whitton, Scott M Lindhorst, Nimisha Deb, Dennis C Shrieve, Hui-Kuo Shu, Beatrice Bloom, Mitchell Machtay, Mark V Mishra, Clifford G Robinson, Minhee Won, Minesh P Mehta
Journal: Neuro-Oncology (2022)

Abstract Background Three- and five-year progression-free survival (PFS) for low-risk meningioma managed with surgery and observation reportedly exceeds 90%. Herewith we summarize outcomes for low-risk meningioma patients enrolled on NRG/RTOG 0539. Methods This phase II trial allocated patients to one of three groups per World Health Organization grade, recurrence status, and resection extent. Low-risk patients had either gross total (GTR) or subtotal resection (STR) for a newly diagnosed grade 1 meningioma and were observed after surgery. The primary endpoint was 3-year PFS. Adverse events (AEs) were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 3. Results Among 60 evaluable patients, the median follow-up was 9.1 years. The 3-, 5-, and 10-year rates were 91.4% (95% CI, 84.2 to 98.6), 89.4% (95% CI, 81.3 to 97.5), 85.0% (95% CI, 75.3 to 94.7) for PFS and 98.3% (95% CI, 94.9 to 100), 98.3%, (95% CI, 94.9 to 100), 93.8% (95% CI, 87.0 to 100) for overall survival (OS), respectively. With centrally confirmed GTR, 3/5/10y PFS and OS rates were 94.3/94.3/87.6% and 97.1/97.1/90.4%. With STR, 3/5/10y PFS rates were 83.1/72.7/72.7% and 10y OS 100%. Five patients reported one grade 3, four grade 2, and five grade 1 AEs. There were no grade 4 or 5 AEs. Conclusions These results prospectively validate high PFS and OS for low-risk meningioma managed surgically but raise questions regarding optimal management following STR, a subcohort that could potentially benefit from adjuvant therapy.
MODL-01. Targeting replication stress in pediatric brain tumors
Authors: Sonja Krausert, Norman Mack, Benjamin Schwalm, Heike Peterziel, Ina Oehme, Cornelis M van Tilburg, Olaf Witt, Stefan M Pfister, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract Previously, we have found that Embryonal Tumors with Multilayered Rosettes (ETMR) tumor cells harboring high levels of R-loops, a potential marker for replication stress and genomic instability, are vulnerable to a combination of topoisomerase and PARP inhibitors. To follow up on this, we investigated whether other pediatric brain tumor types with high levels of R-loops, such as MYC-amplified Group 3 medulloblastoma (MB) and ZFTA-fusion positive ependymoma, are also sensitive to these inhibitors. First, we performed in vitro drug screens using HD-MB03, a Group 3 MB cell line, and the ETMR cell line BT183, and in both screens PARP inhibitors were identified as the most synergistic combination partners for the topoisomerase inhibitor Irinotecan, respectively the active metabolite SN-38. Normal Astrocytes were not sensitive to these combinations. Secondly, we performed in vivo studies using patient-derived xenograft (PDX) models injected subcutaneously or intracranially into NSG mice, and treated with the PARP inhibitor Pamiparib, Irinotecan or a combination of both. For a MYC-amplified Group 3 MB and a ZFTA-fusion positive Ependymoma model, both injected intracranially, treatment with Irinotecan or the combination led to a significant survival benefit and inhibition of tumor growth including transient tumor shrinkage, but addition of Pamiparib did not add any further benefit in vivo, even though intratumoral PARP was inhibited by at least 80%. In contrast, in the subcutaneously injected ETMR model, the combination treatment with Irinotecan and Pamiparib led to a synergistic effect and complete regression of the tumors. Further refinements of the treatment strategy as dose adaptations and the use of a pegylated version of SN-38 (PLX038A) did also not induce a synergistic effect of the drugs for the intracranial tumors. Additional in vivo studies to evaluate the differences in efficacy and whether these are tumor specific or due to incomplete brain penetrance of the drugs are ongoing.
OTHR-44. Building narrative competence on the neuro-oncology team: a narrative medicine approach to fostering unity and resilience for work with pediatric brain tumor families
Authors: Kathy Riley
Journal: Neuro-Oncology (2022)

Abstract Narrative medicine relies on recognizing, taking in, reflecting on and responding to the stories of suffering in others. Drawing on the practice of the close reading of literature and reflection through writing, healthcare professionals gain fresh insights into their own stories and in turn connect in meaningful ways to stories of illness in their patients (Charon, 2001). The lived experience of pediatric neuro-oncology teams seesaws between hard-fought victories and stories of pain, loss, and even death. For patients who survive, many face life-long challenges that impact long-term quality of life. Learning to be an eyewitness of both beauty and pain in literature and art and writing about that witness helps teams reflect on the stories that shape them and their patients as they process the unthinkable in their work. This type of narrative competence requires what Sayantani DasGuspta refers to as narrative humility (Das Gupta, 2008). Narrative humility recognizes that stories of illness are ambiguous, contain contradictions, and belong wholly to the patient, and encourage providers to explore the role their own narrative brings to the clinician-patient relationship (Das Gupta, 2008). This narrative competence enables team members to find new ways to navigate their practice and foster team unity. Connecting to their own narrative allows them to connect to the narratives of others. They learn to be uncomfortable, to feel pain or joy, and to find power in being physically present with someone who is healed, feels marginalized, or is wounded. By listening closely to the stories of illness and loss in others and reflecting on their own stories through narrative medicine techniques, they learn to engage with the stories that define both their patients and their team dynamics. This theoretical and practical presentation explores the principles of narrative medicine and applies them to the particular experience of neuro-oncology teams.
The role of circular RNAs in pulmonary hypertension
Authors: Md Khadem Ali, Katharina Schimmel, Lan Zhao, Chun-Kan Chen, Kamal Dua, Mark R. Nicolls, Edda Spiekerkoetter
Journal: European Respiratory Journal (2022)

Circular RNAs (circRNAs) are endogenous, covalently circularised, non-protein-coding RNAs generated from back-splicing. Most circRNAs are very stable, highly conserved, and expressed in a tissue-, cell- and developmental stage-specific manner. circRNAs play a significant role in various biological processes, such as regulation of gene expression and protein translation via sponging of microRNAs and binding with RNA-binding proteins. circRNAs have become a topic of great interest in research due to their close link with the development of various diseases. Their high stability, conservation and abundance in body fluids make them promising biomarkers for many diseases. A growing body of evidence suggests that aberrant expression of circRNAs and their targets plays a crucial role in pulmonary vascular remodelling and pulmonary arterial hypertension (group 1) as well as other forms (groups 3 and 4) of pulmonary hypertension (PH). Here we discuss the roles and molecular mechanisms of circRNAs in the pathogenesis of pulmonary vascular remodelling and PH. We also highlight the therapeutic and biomarker potential of circRNAs in PH.
Effect of hepatic impairment on the pharmacokinetics of ripretinib.
Authors: Xiaoyan Li, Charles M Psoinos, Mark Joel Shelton, Farida Abane, Mark A. Matson, Samuel Oberstein, Rodrigo Ruiz-Soto
Journal: Journal of Clinical Oncology (2022)

e16031 Background: Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of patients with advanced gastrointestinal stromal tumor who have received prior treatment with ≥3 kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are CYP3A substrates and coadministration with itraconazole (CYP3A inhibitor) increased exposure to each analyte by ̃100%. Therefore, we studied ripretinib in subjects with varying degrees of hepatic impairment (HI). Methods: Subjects with mild, moderate, and severe HI based on Child-Pugh, and matched healthy subjects received a single oral dose of ripretinib (50 mg, fasting) with 8 days of PK sampling. Concentrations of ripretinib and DP-5439 in plasma were measured by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. PK parameters were calculated using Phoenix WinNonlin, and the geometric least squares mean ratios and corresponding 90% confidence intervals of C max , AUC 0-t , and AUC 0-∞ (total and unbound) were calculated. Unbound concentrations were assessed at T max and 24 hours postdose. Results: Eight subjects with mild HI, 8 with moderate HI, 4 with severe HI, and 13 healthy matches were enrolled. As shown in the table, total ripretinib and DP-5439 PK was comparable for mild HI vs. healthy matches. For moderate HI, total ripretinib AUC was ̃100% higher (C max was comparable), whereas DP-5439 AUC was marginally higher (C max was 32% lower). For severe HI, total ripretinib AUC 0-t was ̃160% higher and C max was ̃24% lower, whereas DP-5439 AUCs were ̃50% lower and C max was 78% lower. Unbound fraction was &lt; 0.6% for ripretinib and 0.2-1.4% for DP-5439, with no clear trend with HI severity. The safety profile in HI subjects was similar to healthy matches; common adverse events (in ≥2 subjects) included increased lipase or amylase, diarrhea, and headache. Conclusions: Consistent with current labeling, mild HI had no impact on total PK. In this study, moderate and severe HI increased ripretinib AUC ̃100% and 163%, respectively. PK exposure to DP-5439 and combined ripretinib + DP-5439 was impacted to a lesser extent. Dose recommendations in moderate and severe HI are currently under development.[Table: see text]
What to Know About the Alzheimer Drug Aducanumab (Aduhelm)
Authors: Steven Woloshin, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2022)

What Should I Know About Alzheimer Disease?Alzheimer disease is the most common cause of memory loss and dementia in older adults.It is progressive and can have a major negative effect on quality of life and independence. How Is Alzheimer Disease Diagnosed and Currently Treated?Diagnosis is based on evaluations that include tests of memory, problem-solving, attention, and language skills.Exercise, brainstimulating activities, and occupational/cognitive behavioral therapy may help limit progression.Two US Food and Drug Administration (FDA)-approved drugs (donepezil and rivastigmine) may slightly slow symptom progression in those with mild disease.Evidence about long-term effects on thinking, behavior, or independent living is insufficient.No known treatments reverse Alzheimer disease.
The detrimental effect of frailty status on renal function recovery after partial nephrectomy – long-term results from a prospective surgical cohort
Authors: G. Rosiello, G. Fallara, G. Basile, A. Martini, D. Cignoli, L. Nocera, F. Belladelli, G. Colandrea, D. Canibus, C. Re, G. Musso, F. Cei, C. Giancristofaro, A. Briganti, R. Bertini, A. Necchi, D. Raggi, P. Karakiewicz, F. Montorsi, A. Salonia, A. Larcher, U. Capitanio
Journal: European Urology (2022)
INSP-08. Cerebellar mutism syndrome: incidence, symptoms, risk factors, prognosis. Results and future perspectives from the Nordic-European study of the cerebellar mutism syndrome
Authors: Astrid Sehested, Jonathan Grønbæk, Aske Laustsen, Marianne Juhler
Journal: Neuro-Oncology (2022)

Abstract Cerebellar mutism syndrome (CMS) can be a devastating consequence of paediatric fossa posterior tumour surgery. This prospective observational multi-centre study was designed to investigate incidence, symptoms, risk factors and prognosis of CMS. It has been running since 2014 and is currently involving 28 centres in 10 countries. So far 600 patients have been included as of 1.2.22, and with the aim of including a total of 1000 the study is still ongoing. Analysis of the first 500 patients has described the incidence, course and associated risk factors of postoperative speech impairment (POSI). Midline location, histological diagnosis of medulloblastoma and ATRT and younger age are associated with increased risk of POSI in our cohort. Route of surgical access specifically comparing telovelar to transvermian approach does not seem to influence the risk of POSI. Second surgery is associated with a lower risk of POSI than primary surgery, whereas we found no difference in risk of cranial nerve dysfunction. Left-handedness is not associated with an increased risk of POSI. Further and ongoing analysis include language analyses of recorded patient speech samples, detailed imaging analysis and description of associations between POSI and other neurological symptoms. The results aim to facilitate pre-operative risk assessment and postoperative robust scoring methods for use in clinical trials. Presented on behalf of the CMS study group, clinicaltrials.gov: Nordic study of the cerebellar mutism syndrome.
Radical cystectomy vs systemic therapy in non-metastatic bladder cancer with advanced lymph nodal disease (cN2/N3 disease) using inverse probability weighting analysis
Authors: H. Garg, F. Dursun, A. Elshabrawy, H. Wang, M. Liss, D. Kaushik, R. Svatek, A. Mansour
Journal: European Urology (2022)
Association of interleukin-enhanced factor 2 (ILF2) expression with prognosis and clinico-genomic features in breast cancer (BC).
Authors: Matias A. Bustos, Jun Yin, Pavel Brodskiy, Irene Kang, Stephanie L. Graff, Sarah Sammons, Richa Dawar, David Spetzler, Dave S. B. Hoon
Journal: Journal of Clinical Oncology (2022)

1030 Background: Novel prognostic and predictive biomarkers beyond traditional histological subtypes are needed to better inform outcomes and enhance therapy guidance in breast cancer (BC). We have previously reported that ILF2 was overexpressed in TNBC cell lines and has a functional role in DNA and RNA metabolism, making it a promising biomarker for risk assessment and treatment decisions. Herein, we aim to leverage a large clinico-genomic dataset to further characterize ILF2 in BC patients (pts). Methods: A total of 9456 BC tissue samples underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next generation sequencing of DNA (592 Gene Panel, or Whole Exome Sequencing), and RNA (Whole Transcriptome Sequencing), and immunohistochemistry (IHC). Wilcoxon and Fisher’s exact were used to determine statistical significance. Overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated. Spearman correlation was used to identify highly correlated genes (ρ&gt;0.6) with ILF2 and significant genes that were subsequently analyzed via pathway analysis using STRING. Results: BC pts were grouped into ILF2-High (H, top quartile) and ILF2-Low (L, bottom quartile) based on mRNA expression (TPM). ILF2-H pts were significantly younger (73 vs 80% for pts &gt;50), enriched in ductal histology (90.9 vs 77.7%), TNBC subtype (48.9 vs 18.9%), and had a higher CNS metastases rate (4.3 vs 1.4%) compared to ILF2-L pts (all q&lt;0.0001). ILF2 overexpression was associated with significantly inferior OS in all BC pts (HR 3.38, 95%CI: 2.97 – 3.84); when stratified into known BC hormonal receptor (HR) subtypes, ILF2 was prognostic in both HR+ BC (HR 1.7, 95 CI: 1.34-2.19) and TNBC (HR 3.8, 95 CI: 3.1-4.7), all p&lt;0.0001. In TNBC (n=2468), ILF2-H was associated with a higher frequency of TP53 mutations(mt), lower rate of PIK3CA mt and higher amplification of CCNE1 and FGF23; in HR+/HER2- BC (n = 5071), an association with a higher rate of TP53 mt, PD-L1 expression, NOTCH2 and CCND2 amplification was seen (Table). No significant molecular correlation with ILF2 was seen in HR-/HER2+ BC (n=682). In TNBC, ILF2 expression was significantly correlated with genes involved in spliceosome, cell cycle and RNA transport pathways. In HR+/HER2- BC, ILF2-correlated genes were significantly enriched in mismatch repair and DNA replication pathways (p&lt;0.05 for all factors individually). Conclusions: High expression of ILF2 is associated with a poorer prognosis independent of subtype in BC and our study warrants further investigation on ILF2 as a diagnostic and therapeutic target.[Table: see text]
Clinicopathological characteristics and prognostic factors of 130 patients with Krukenberg tumors of gastric origin.
Authors: Xiaolin Lin, Ting Han, Meng Zhuo, Tengfei Liu, Zebing Liu, Dongxi Xiang, Hong Li, Xiuying Xiao
Journal: Journal of Clinical Oncology (2022)

e16023 Background: Krukenberg tumors of gastric origin have a poor prognosis. Their clinicopathologic characteristics are rarely reported and they lack optimal clinical management. There is an urgent need to explore new strategies to improve patient survival and quality of life. Methods: The clinicopathological characteristics, treatments and survival data were collected and analyzed from 130 patients with Krukenberg tumors of gastric cancer. Results: The median age of the patients was 41 years. A total of 63.1% of patients had synchronous ovarian metastasis, 70.8% had bilateral ovarian metastasis, 68.5% had peritoneum metastasis, and 98.4% had pathologically poorly differentiated adenocarcinoma. The positive rate of HER-2 was 1.8%. Only one patient showed dMMR. The follow-up rate was 90.8%. The median OS from the diagnosis of ovarian metastasis was 13.0 months. Univariate analysis showed that the significant survival factors included menstrual status, size of the gastric lesion and ovarian metastasis, number of lymph node metastases, interval time to ovarian metastasis, resection of gastric foci, peritoneal metastasis, oophorectomy, chemotherapy after ovarian metastasis, 2-drug regimen chemotherapy, albumin, serum CA-125 level, platelet count, D-dimer, fibrinogen, pretreatment high FAR, PLR and SII. Further multivariable analysis found that albumin, peritoneal metastasis and oophorectomy were independent prognostic factors. Conclusions: Patients of gastric cancer with Krukenberg tumors had some unique clinical characteristics. Active improvement of hypoalbuminemia, treatment of hypercoagulability, management of peritoneal metastasis, timely oophorectomy and chemotherapy can improve the patients’ prognosis. This suggests that we should focus on the nutritional status and coagulation function of patients with Krukenberg tumors in our clinical work.